2018ASCO晚期乳腺癌治疗进展

Click to edit Master title style,Edit Master text styles,Second level,Third level,Fourth level,Fifth level,2018/9/1,#,2018/9/1,#,单击此处编辑母版标题样式,编辑母版文本样式,第二级,第三级,第四级,第五级,2018/9/1,#,ASCO,晚期乳腺癌治疗进展,内分泌及化疗篇,中山大学肿瘤防治中心内科,史艳侠,2018-9-2,内容,ASCO,内分泌治疗进展,ASCO,化疗进展,Abs 1003,：,Utidelone(UTD1),联合卡培他滨（,CAP,）,VS,卡培他滨治疗蒽环类和紫衫类难治性晚期乳腺癌（,MBC,）,BG01-1323L,随机,III,期临床研究的,OS,结果,Abs 1000,：,Ribociclib,联合氟维司群治疗激素受体阳性，,HER2,阴性的晚期乳腺癌患者的,MONALEESA-3,研究结果,Abs 1002,：,Abemaciclib,用于,HR +,，,HER2-,晚期乳腺癌绝经前,/,围绝经期女性,内容,ASCO,内分泌治疗进展,ASCO,化疗进展,Abs 1003,：,Utidelone(UTD1),联合卡培他滨（,CAP,）,VS,卡培他滨治疗蒽环类和紫衫类难治性晚期乳腺癌（,MBC,）,BG01-1323L,随机,III,期临床研究的,OS,结果,Abs 1000,：,Ribociclib,联合氟维司群治疗激素受体阳性，,HER2,阴性的晚期乳腺癌患者的,MONALEESA-3,研究结果,Abs 1002,：,Abemaciclib,用于,HR +,，,HER2-,晚期乳腺癌绝经前,/,围绝经期女性,不同激酶活性的选择性,CDK4/6,抑制剂,礼来,辉瑞,诺华,药物,Cyclin-Dependent Kinase IC,50, nM,CDK4,CDK6,CDK9,Abemaciclib,2,9.9,57,Palbociclib,11,15,NR,Ribociclib,10,39,NR,Gelbert LM, et al. Invest New Drugs. 2014;32:825-837.,Fry DW, et al. Mol Cancer Ther. 2004;3:1427-1438.,Kim S, et al. AACR-NCI-EORTC 2013. Abstract PR02.,CDK4/6,抑制剂研究历程,6,1L or 2L HR+,，,HER2- mBC,Ribociclib+,fulvestrant,MONALEESA-3,2018,Other trials ongoing,CDK4/6,抑制剂,ASCO,发布两项重要数据,12.8m-20.5m,0.59,MONARCH3,JCO 2017,NSAI,Abemaciclib,14.7m- 28.2m,0.54,Ribociclib,联合氟维司群治疗激素受体阳性，,HER2,阴性的晚期乳腺癌患者的,MONALEESA-3,研究结果,Dennis J. Slamon, Patrick Neven, Stephen K. L. Chia, Seock-Ah Im, Peter A. Fasching, Michelino DeLaurentiis, Katarina Petrakova, Giulia Valeria Bianchi, Francisco J. Esteva, Miguel Martin, Xavier Pivot, Gena Vidam, Yingbo Wang,1000,MONALEESA-3,：,III,期安慰剂对照的,Ribociclib,联合氟维司群的研究,Dennis J, et al. 2018 ASCO Abstract,1000,绝经,HR+/HER2-,的晚期乳腺癌（,ABC,）,没有经过治疗或者,1,线的内分泌治疗,N=726,Ribociclib,（,600mg/,天口服；治疗,3,周停,1,周）,+,氟维司群（,500mg,）*,N=484,安慰剂,+,氟维司群（,500mg,）*,N=242,随机,2:1,首要研究终点：,PFS,（当地评估根据,RECIST1.1,）,次要研究终点：,OS,ORR,CBR,至缓解时间（,TTR,）,缓解持续时间（,DOR,）,ECOG PS,的明确的恶化时间,病人报告结果,安全性,药代动力学,分层因素：,是否有肝肺转移；,先前是否有内分泌治疗,肿瘤的评估在前,18,个月每,8,周一次，之后每,12,周一次；,初步的分析计划是在发生,364,个,PFS,事件之后,95,的可信区间检测到,33,的风险减少（,HR 0.67,）与单侧,= 2.5,，相当于增加中位,PFS,到,13.4,月（中位,PFS,在安慰剂组为,9,个月），样本大小为,660,个病人,先前内分泌治疗状态标准,一线,（,未接受过,晚期乳腺癌的治疗）,二线,+,早期复发,（接受,1,线的晚期乳腺癌的内分泌治疗）,复发,:,新辅助,/,辅助内分泌治疗完成,12,个月,或,先前没有接受过晚期转移性疾病的治疗（没有先前的药物暴露和内分泌治疗）,早期复发在新辅助,/,辅助内分泌治疗期间或,12,月内,或,复发发生在完成新辅助,/,辅助内分泌治疗,12,个月并有在一线内分泌治疗（抗雌激素,/AI,）后出现亚进展的晚期乳腺癌患者,或,晚期乳腺癌诊断为一线内分泌治疗后进展（抗雌激素,/AI,）,Dennis J, et al. 2018 ASCO Abstract,1000,首要研究终点：,PFS,（研究者评估）,Dennis J, et al. 2018 ASCO Abstract,1000,PFS,亚组分析,Dennis J, et al. 2018 ASCO Abstract,1000,根据先前内分泌治疗状态的,PFS,Dennis J, et al. 2018 ASCO Abstract,1000,次要研究终点：,ORR,和,CBR,Dennis J, et al. 2018 ASCO Abstract,1000,在所有患者中,CBR,在,Ribociclib+,氟维司群组为,70.2%,，安慰剂,+,氟维司群组为,62.8%,（,P=0.020,）,在有可测量病灶的患者中,CBR,在,Ribociclib+,氟维司群组为,69.4%,，安慰剂,+,氟维司群组为,59.7%,（,P=0.015,）,血液学毒性,（无论研究治疗关系）,AE5%,在整个治疗组中,Ribociclib+,氟维司群,N=483,安慰剂,+,氟维司群,N=241,全部,3,级,4,级,全部,3,级,4,级,中性粒细胞减少,69.6,46.6,6.8,2.1,0,0,白细胞减少,28.4,13.5,0.6,1.7,0,0,贫血,17.2,3.1,0,5.4,2.1,0,血小板减少,8.5,0.8,0.2,1.7,0,0,Dennis J, et al. 2018 ASCO Abstract,1000,发热性中性粒细胞减少症发生在,Ribociclib+,氟维司群组的,5,例患者（,1%,）中，安慰剂组没有发生,非血液学毒性,Dennis J, et al. 2018 ASCO Abstract,1000,AE25%,在整个治疗组中,Ribociclib+,氟维司群,N=483,安慰剂,+,氟维司群,N=241,全部,3,级,4,级,全部,3,级,4,级,恶心,45.3,1.4,0,28.2,0.8,0,疲乏,31.5,1.7,0,33.2,0.4,0,腹泻,29.0,0.6,0,20.3,0.8,0,呕吐,26.7,1.4,0,12.9,0,0,关节痛,24.0,0.6,0,26.6,0.4,0,基线后,QTcF480ms,基于,ECG,数据，发生在,Ribociclib+,氟维司群组的,27,例（,5.6%,）患者中，,安慰剂,+,氟维司群组发生,6,例（,2.5%,）,3/4,级的,ALT/AST,升高发生在,Ribociclib+,氟维司群组的,32,例（,6.6%,）,/9,例（,1.9%,），安慰剂,+,氟维司群组的,23,例（,4.8%,）,/6,例（,1.2%,）患者中,两例患者在,Ribociclib+,氟维司群组发生确定的,Hys,；,AST,ALT,和,TBIL,水平在,Ribociclib,停药后都恢复正常,结论,病人接受,Ribociclib+,氟维司群治疗对比安慰剂,+,氟维司群有统计学上显著的和有临床意义的,PFS,的提高；,HR,：,0.593,；,P=0.00000041,；对比安慰剂疾病复发风险减少,41%,Ribociclib,治疗的获益与亚组患者一致,一线,Ribociclib +,氟维司群治疗观察到,PFS,的延长（,HR,：,0.577,；,95%CI,：,0.415-0.802,）,在接受二线治疗的患者中也可以观察到同样的,PFS,的获益（,HR,：,0.565,；,95%CI,：,0.428-0.744,）,Ribociclib+,氟维司群治疗证实安全性可控，与之前的,III,期研究一致,Ribociclib+,氟维司群可能可以成为绝经后,HR+/HER2-,晚期乳腺癌患者新的一线和二线的治疗选择,这是第一项,CDK4/6,抑制剂联合氟维司群在未经治疗的晚期乳腺癌和完成,12,个月新辅助,/,辅助内分泌治疗的乳腺癌患者中显示出疗效的研究,Dennis J, et al. 2018 ASCO Abstract,1000,Abemaciclib,用于,HR +,，,HER2-,晚期乳腺癌绝经前,/,围绝经期女性,Patrick Neven, Hope S. Rugo, Sara M. Tolaney, Hiroji Iwata, Masakazu Toi, Matthew P. Goetz, Peter A. Kaufman, Susana Barriga, Yong Lin, George W.,1002,1. Altucci L et al.,Oncogene,1996;12(11):2315-24 2. Meyerson M et al.,Mol Cell Biol,1994;14(3):2077-86,3. Torres-Guzmn R et al. Oncotarget 2017;8(41):69493-507,4. Gelbert et al. Invest New Drugs 2014;32(5):825-37,5.,Dickler MN et al. Clin Cancer Res 2017;23(17):5218-24,6. Sledge GW, Jr., et al. J Clin Oncol. 2017;35(25):2875-84,7. Goetz MP, et al. J Clin Oncol 2017; 35(32):3638-46,G1,S,M,G2,E2F,Cyclin D,CDK6,Cell Proliferation,Cyclin D,CDK4,E2F,RB,PO,4,PO,4,PO,4,RB,Estrogen,ER,CDK4/6,抑制剂治疗,HR+,乳腺癌,在,HR +,乳腺癌中，雌激素刺激细胞周期蛋白,D1,表达并激活,CDK4,和,6,以及随后的细胞周期进程,1,2,Abemaciclib,是,CDK4,6,选择性抑制剂，每天两次，连续给药；,用,Abemaciclib,持续抑制,CDK4,和,6,导致持续的细胞周期停滞和随后的衰老或细胞凋亡,3,，,然而，短期抑制导致可逆的反弹效应,4,Abemaciclib,在,HR +,，,HER2-,晚期乳腺癌（,ABC,）患者中显示出单药治疗（,MONARCH 1,）,5,和联合氟维司群,MONARCH 2,6,或,NSAI MONARCH 3,7,的疗效和耐受性,在这里，我们报道,MONARCH2,研究中前,/,围绝经期女性的疗效和安全性数据,Patrick Neven, et al. 2018 ASCO Abstract,1002,Abemaciclib,作为单药治疗的,MONARCH 1,研究,Patrick Neven, et al. 2018 ASCO Abstract,1002,Sept 2006: 51yrs WE ALND : pILA pT2N1a (1/14),Adj CT with 3x FEC-100,3x Taxotere 100mg/m,Adjuvant RT and 5yrs Anastrozole,06-2012: Bone Met Exemestane,01-2014: PD Bone Tamoxifen,05-2014: PD Liver, lung Taxol qw,09-2014: PD Liver, pleura, lung Abemaciclib mono,06-2017: PD Liver Fulvestrant,10-2017: PD Liver, lung Exemestane Everolimus,01-2018: PD: Liver, pleura, lung Carbo - Gemcitabine,04-2018: PD,Capecitabine,PR,持续时间,PFS,时间为,33,个月,MONARCH 2,实验设计：,HR+/HER2- ABC,绝经前,a,或绝经后,内分泌治疗（,ET,）耐药,:,新辅助或辅助内分泌治疗,1,年内复发,一线内分泌治疗期间进展,未接受化疗的,MBC,不超过,1,种内分泌治疗的,MBC,ECOG PS 1,abemaciclib: 150mg,b,BID,(,连续给药,),氟维司群,: 500mg,c,首要终点,:,研究者评估,PFS(,Investigator-assessed PFS),次要终点,:,OS, Response,Clinical Benefit Rate, Safety,分层因素,:,-,转移灶,-,内分泌治疗耐药,(primary vs secondary),1,2,placebo: BID,(,连续给药,),氟维司群,: 500mg,c,随机,2:1,N=669,统计设计,:,假设真实的,HR,为,0,.703,，,90%,的效力检测出单侧,为,0.025%,需要,378,个事件,病人在,19,个国家的,142,个研究中心入组,a,年龄,60,岁，并有自然月经出血。 患者需要接受促性腺激素释放激素（,GnRH,）激动剂,b,在所有新进和持续的患者中，通过协议修订减少剂量，其中,178,名患者入组后，从,200mg,减少到,150mg BID,c,每个患者给予氟维司群,Patrick Neven, et al. 2018 ASCO Abstract,1002,Cardoso F et al.,Breast.,2017;31:244-59,Cardoso F et al.,Ann Oncol,. 2017;28:16-33,placebo +,氟维司群,n,=,42,abemaciclib +,氟维司群,n,=72,中位年龄,(,范围,),46 (3257),47 (3266),种族, n (%),亚洲,51 (70.8),24 (57.1),高加索,14 (19.4),16 (38.1),其他,7 (9.7),2 (4.7),最近的内分泌治疗, n (%),a,新辅助或辅助,44 (61.1),21 (50.0),转移,26 (36.1),20 (47.6),先前,AI,治疗, n (%),是,10 (13.9),12 (28.6),否,62 (86.1),30 (71.4),对内分泌治疗敏感, n (%),a,原发耐药,b,28 (38.9),15 (35.7),继发耐药,c,42 (58.3),26 (61.9),PgR,状态, n (%),阳性,54 (75.0),38 (90.5),阴性,18 (25.0),4 (9.5),转移灶, n (%),内脏,43 (59.7),17 (40.5),仅有骨,19 (26.4),15 (35.7),其他,10 (13.9),10 (23.8),可测量病灶, n (%),是,51 (70.8),28 (66.7),否,21 (29.2),14 (33.3),Abbreviations: AI, aromatase inhibitor; ET, endocrine therapy; PgR, progesterone receptor,a,2 patients in the abemaciclib arm and 1 patient in the placebo arm received no prior ET,b,patients whose disease relapsed 2 years while receiving (neo)adjuvant ET or progressed 6 months of receiving ET for ABC (Cardoso F, et al. Breast. 2017;31:244-59; Cardoso F, et al. Ann Oncol. 2017;28:16-33),c,patients receiving prior ET who do not meet the definition of primary resistance were considered to have secondary resistance,绝经前,/,围绝经期人群的基线特征,Patrick Neven, et al. 2018 ASCO Abstract,1002,ITT,人群的,PFS,Patrick Neven, et al. 2018 ASCO Abstract,1002,中位,PFS,abemaciclib +,氟维司群,: 16.4 months,placebo +,氟维司群,: 9.3 months,HR (95% CI): .553 (.449, .681);,p.0000001,PFS,的获益经过盲法独立中心评估确认,HR: .460; 95% CI: .363, .584;,p.000001,Sledge GW Jr. et al.,J Clin Oncol,2017;35(25):2875-84,绝经前,/,围绝经期人群的,PFS,Patrick Neven, et al. 2018 ASCO Abstract,1002,PFS,的获益经过盲法独立中心评估确认,HR: .432; 95% CI: .236, .793;,p20%,318,235,0.53 (0.380.74),0.57 (0.410.79),HR (95% CI),Favors PAL+LET,Favors PCB+LET,Percentile,n,HR,(95% CI),All patients,666,0.58 (0.46,0.72),ER status,25,th,25,th,to 25,th,to 25,th,to 25,th,to 75,th,75,th,140,258,152,0.74 (0.461.20),0.62 (0.440.89),0.33 (0.21,0.52),HR (95% CI),Favors PAL+LET,Favors PCB+LET,Qualitative analysis,Quantitative analysis,0.0,0.5,1.0,1.5,0,1,2,3,4,Q5,何种肿瘤更获益？,Biomarker,仍在探索,2017,年,SABCS,：亚组分析,-,肝转移等优势受益人群,MONARCH 2,氟维司群,abemaciclib,MONARCH 3,1,2,NSAI ,abemaciclib,基线无肝转移,基线肝转移,100,80,60,40,20,0,0,4,8,12,16,20,24,28,时间,(,月,),PFS (%),HR=0.44,(95% Cl 0.31-0.64),Abemaciclib (n=115),中位,11.6,个月,安慰剂,(n=59),中位,3.1,个月,100,80,60,40,20,0,0,4,8,12,16,20,24,28,时间,(,月,),PFS (%),HR=0.46,(95% Cl 0.25-0.88),Abemaciclib (n=48),中位,16.0,个月,安慰剂,(n=30),中位,7.2,个月,100,80,60,40,20,0,0,4,8,12,16,20,24,28,时间,(,月,),PFS (%),HR=0.55,(95% Cl 0.43-0.71),Abemaciclib (n=331),中位,19.9,个月,安慰剂,(n=164),中位,11.6,个月,100,80,60,40,20,0,0,4,8,12,16,20,24,28,时间,(,月,),PFS (%),HR=0.66,(95% Cl 0.41-0.73),Abemaciclib (n=280),中位未达到,安慰剂,(n=135),中位,15.3,个月,1. Goetz MP, et al. J Clin Oncol 2017;35(32):3638-46.,2. Di Leo A, et al. Annals of Oncology 2017;28(suppl_5):v605-v649.,临床病理特征包括：肝转移、,PR-,、高肿瘤分级、,MONARCH 2,TFI,36m,、,内容,ASCO,内分泌治疗进展,ASCO,化疗进展,Abs 1003,：,Utidelone(UTD1),联合卡培他滨（,CAP,）,VS,卡培他滨治疗蒽环类和紫衫类难治性晚期乳腺癌（,MBC,）,BG01-1323L,随机,III,期临床研究的,OS,结果,Abs 1000,：,Ribociclib,联合氟维司群治疗激素受体阳性，,HER2,阴性的晚期乳腺癌患者的,MONALEESA-3,研究结果,Abs 1002,：,Abemaciclib,用于,HR +,，,HER2-,晚期乳腺癌绝经前,/,围绝经期女性,Utidelone(UTD1),联合卡培他滨（,CAP,）,VS,卡培他滨治疗蒽环类和紫衫类难治性晚期乳腺癌,BG01-1323L,随机,III,期临床研究的,OS,结果,Binghe Xu, Pin Zhang, Tao Sun, Qingyuan Zhang, Zefei Jiang, Zhongyu Yuan, Xiaojia Wang, Shude Cui, Yuee Teng, Xi-Chun Hu, Junlan Yang, Hongming Pan, Zhongsheng Tong, Huiping Li, Qiang Yao, Yongsheng Wang,1003,研究背景,试剂：,Utidelone(UTD1),是一种应用发酵方法制备的埃博霉素类似物,且是一种微管抑制剂及血管生成抑制剂；,异种移植模型：广谱的抗癌活性，对于人类乳腺癌，肺癌、肝癌、结肠癌以及前列腺癌，可使肿瘤体积减小,70%-90%,；,临床,I,期、,II,期单药疗法：,UTD1,对于紫杉醇和蒽环霉素治疗后的晚期乳腺癌患者：临床,I,期，例数,15,，客观缓解率（,ORR,）为,23.4%,；临床,II,期,:,例数,70,，,ORR,为,28.6%,， 无进展生存期,(PFS),为,5.6,个月；,联合,II,期研究：,UTD1,联合卡培他滨治疗紫杉醇和蒽环类治疗过的患者：例数,33,，,ORR,为,43.8%,，,PFS,为,7.9,月；,联合,III,期研究：,UTD1,联合卡培他滨（,CAP,）对比卡培他滨单药治疗经过紫衫类和蒽环类治疗的晚期乳腺癌患者（,MBC,）能显著延长,PFS,和提高,ORR,。,Binghe Xu, et al. 2018 ASCO Abstract,1003,研究对象和研究终点,Binghe Xu, et al. 2018 ASCO Abstract,1003,研究对象：,诊断为进展期转移性乳腺癌,(MBC),；,经过,蒽环,类及,紫杉,类治疗的难治性,MBC,；,使用化疗药方案,4,，且均为治疗失败后；,研究终点：,总生存（,OS,）,无进展生存期（,PFS,）,IRRC,的实体瘤疗效评价标准,RECIST1.1,客观缓解率（,ORR,）；,安全性参数,使用,NCI CTC4.03,标准,给药方案,Binghe Xu, et al. 2018 ASCO Abstract,1003,治疗方案（方案,A,）,：,270,例,UTD1,联合,CAP,UTD1:30mg/m,2,/,天,iv. day1,5,CAP:1000mg/m,2,口服,bid day1,14,每,21,天,/,周期；,对照方案（方案,B,）,:135,例,CAP,单药治疗,CAP:1250mg/m,2,口服,bid day1,14,；,作为对照组；,每,21,天,/,周期；,有,SD,、,PR,或者,CR,的患者可以继续接受治疗至,12,个周期，除非疾病 进展或者难以忍受的药物毒性,12,个治疗周期后，根据研究者的建议病人可以继续治疗,第一例病人治疗时间：,2014.8.8,最后一例病人治疗时间：,2015.12.14,PFS,截止时间：,2016.9.15,）,Binghe Xu, et al. 2018 ASCO Abstract,1003,0,3,6,9,12,15,18,21,24,PFS (,月,),0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,PFS,UTD1+CAP, n=243,CAP, n=116,IRRC-PPS,UTD1+CAP,CAP,进展或死亡, n,197,110,中位,(,月,),8.57,4.11,95% CI,7.92, 9.49,2.96, 5.49,HR, 95% CI,0.46,0.36, 0.58,P,值,0.0001,0,3,6,9,12,15,18,21,24,0.0,PFS (,月,),0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,PFS,UTD1+CAP, n=270,CAP, n=135,IRRC-FAS,UTD1+CAP,CAP,进展或死亡, n,214,115,中位,(,月,),8.44,4.14,95% CI,7.89,9.49,3.09, 5.09,HR, 95% CI,0.47,0.37, 0.59,P,值,0.0001,确定的客观反应（,RECIST1.1,）,（截止时间：,2016.9.15,）,最佳反应,基于研究者,基于,IRRC,FAS,UTD1+CAP,N=270,CAP,N=135,UTD1+CAP,N=270,CAP,N=135,CR,2,1,3,0,PR,106,34,120,32,SD,121,62,116,59,PD,35,29,22,31,NA,6,9,9,13,ORR,40.0%,25.9%,45.6%,23.7%,95%CI,34.1%,，,46.1%,18.8%,，,34.2%,39.5%,，,51.7%,16.8%,，,31.8%,P,值,0.0058,0.0001,临床获益,CR+PR+SD6,月,54.4%,37.0%,60.0%,33.3%,95%CI,48.3%,，,60.5%,28.9%,，,45.6%,53.9%,，,65.9%,25.5%,，,42.0%,P,值,0.0011,0.0001,Binghe Xu, et al. 2018 ASCO Abstract,1003,OS,(,时间：,2018.3.9,）,Binghe Xu, et al. 2018 ASCO Abstract,1003,与伊沙匹隆的数据对比没有改善,OS,0,6,12,18,24,30,33,39,45,3,9,15,21,27,36,42,时间,(,月,),0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,OS,UTD1+CAP, n=243,CAP, n=116,OS-FAS,UTD1+CAP,CAP,PPS,集, n,243,116,死亡, n,165,94,中位,月,21.30,15.90,95% CI,17.80, 23.90,14.40, 19.50,HR, 95% CI,0.68,0.52, 0.87,Log-r P,值,0.0024,0,6,12,18,24,30,33,39,45,3,9,15,21,27,36,42,OS (,月,),0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,OS,UTD1+CAP, n=270,CAP, n=135,OS-FAS,UTD1+CAP,CAP,随机, n,270,135,死亡, n,183,101,中位,月,20.40,16.20,95% CI,17.20, 22.90,14.40, 18.80,HR, 95% CI,0.72,0.57, 0.93,Log-rank P,值,0.0093,AE,事件,-,安全性,（截止时间：,2016.9.15,）,NCI CTC4.03,所有级别,3,级或更高,SAEs,分类,亚分类,UTD1+CAP,N=267,CAP,N=130,UTD1+CAP,N=267,CAP,N=130,UTD1+CAP,N=267,CAP,N=130,任意,TEAE,99.3%,93.8%,53.6%,35.4%,7.1%,10.8%,外周感觉神经病变,85.4%,9.2%,25.1%,0.8%,0.4%,0,掌跖红肿感觉异常,36.3%,40.0%,7.1%,7.7%,0,0,血液学毒性,62.8%,58.3%,16.5%,15.4%,0.4%,1.5%,白细胞减少,50.6%,46.9%,5.2%,5.4%,0.4%,0.8%,中性粒细胞减少,49.4%,43.8%,12.7%,10.8%,0,0.8%,贫血,25.5%,24.6%,3.4%,3.8%,0,0.8%,胃肠道毒性,59.0%,43.2%,9.8%,4.5%,1.5%,3.0%,恶心,28.5%,26.2%,1.5%,1.5%,0,0.8%,腹泻,28.5%,9.2%,7.5%,2.3%,1.1%,1.5%,肝肾毒性,41.4%,41.7%,1.9%,4.6%,0.4%,2.3%,AST,升高,27.3%,20.8%,0.7%,1.5%,0.4%,0.8%,ALT,升高,26.6%,15.4%,0.4%,0.8%,0.4%,0.8%,高胆红素血症,16.1%,29.2%,0.7%,1.5%,0,2.3%,其他,81.2%,62.1%,9.4%,5.3%,3.4%,1.5%,失眠,19.8%,3.8%,0,0,0,0,Binghe Xu, et al. 2018 ASCO Abstract,1003,Binghe Xu, et al. 2018 ASCO Abstract,1003,3,级周围神经病变的持续时间,-,安全设置,（截止时间：,2016.9.15,）,UTD1+CAP,N=267,CAP,N=130,3,级周围神经病变，,n,（,%,）,67,（,25.1%,）,1,（,0.8%,）,AE,解决，,n,（,%,）,64,（,95.5%,）,1,（,100%,）,AE,解决时间（周）,中位持续时间,（周）,3.14,0.71,Min-Max,0.3-35.9,0.7-0.7,AE,事件,-,安全性,（截止时间：,2016.9.15,）,伊沙匹隆导致,3 / 4 PN,级的解决时间为,6,周,结论,Utidelone,联合卡培他滨对比卡培他滨单药治疗经过大量前期治疗的,MBC,患者不仅能,显著延长,PFS,和提高,ORR,，还能,显著延长,OS,，也优于伊沙匹隆的历史数据，伊沙匹隆没有延长,OS,；,在联合组中仅有,周围神经毒性,发生率,高,；,3,级或更高级毒性,中位恢复,为,1,级或更好的时机为,3,周,；,Utidelone,为,MBC,患者提供了一种更好的潜在治疗选择用于治疗蒽环类和紫衫类难治的,MBC,患者,Binghe Xu, et al. 2018 ASCO Abstract,1003,总 结,MONALEESA-3,研究：,CDK4/6,抑制剂联合治疗方案从晚期二线走向晚期一线,MONARCH-2,研究：,CDK4/6,抑制剂从绝经后走到绝经前,BG01-1323L,研究：,UTD1,为,MBC,患者提供了一种更好的潜在治疗选择用于治疗蒽环类和紫衫类难治的,MBC,患者,THANKS,！,2,年生存率,组,FAS,PPS,UTD1+CAP,N=270,CAP,N=135,UTD1+CAP,N=243,CAP,N=116,OS,中位随访时间（,IQR,），月,19.4,（,10.5-32.1,）,14.9,（,8.9-26.0,）,20.7,（,11.5-32.2,）,15.9,（,9.7-26.3,）,2,年生存率,（,95%CI,）,0.421,（,0.361,0.481,）,0.315,（,0.233,0.396,）,0.437,（,0.374,0.500,）,0.306,（,0.221,0.390,）,两组间差异,0.107,（,0.005,0.208,）,0.131,（,0.025,0.236,）,P,值,0.0389,0.0150,Binghe Xu, et al. 2018 ASCO Abstract,1003,人口统计学和选择时基线特征,特征,UTD1+CAP,（,N=270,）,CAP,（,N=135,）,年龄（年）,中位（范围）,50,（,25-70,）,50,（,27-69,）,65,258,（,95.6%,）,131,（,97.0%,）,65,12,（,4.4%,）,4,（,3.0%,）,ECOG,丢失,5,（,1.9%,）,2,（,1.5%,）,0,91,（,33.7%,）,39,（,28.9%,）,1,168,（,62.2%,）,90,（,66.7%,）,2,6,（,2.2%,）,4,（,3.0%,）,HER2-,未知,38,（,14.1%,）,22,（,16.3%,）,阳性,76,（,28.1%,）,40,（,29.6%,）,阴性,155,（,57.4%,）,73,（,54.1%,）,HER ER PR,阴性,49,（,18.1%,）,23,（,17.0%,）,先前化疗方案数量,1,60,（,22.2%,）,25,（,18.5%,）,2,99,（,36.7%,）,54,（,40.0%,）,3,68,（,25.2%,）,23,（,17.0%,）,4,43,（,15.9%,）,33,（,24.4%,）,先前经过蒽环类和紫衫类治疗,268,（,99.3%,）,135,（,100%,）,先前经过卡培他滨治疗,28,（,10.4%,）,21,（,15.6%,）,肿瘤转移,淋巴结,161,（,59.6%,）,79,（,58.5%,）,肺,145,（,53.7%,）,70,（,51.9%,）,骨,131,（,48.5%,）,76,（,56.3%,）,肝,123,（,45.6%,）,68,（,50.4%,）,胸膜,26,（,9.6%,）,15,（,11.1%,）,脑,6,（,2.2%,）,1,（,0.7%,）,肾,2,（,0.7%,）,2,（,1.5%,）,其他,68,（,25.2%,）,39,（,28.9%,）,Binghe Xu, et al. 2018 ASCO Abstract,1003,研究药物暴露小结,药物暴露,A,组：,UTD1+CAP,B,组：,CAP,中位周期数，,n,（范围）,6,（,0-29,）,6,（,0-25,）,8,次,UTD1,周期,29.2%,8,次,CAP,周期,40.1%,39.2%,1,次,UTD1,剂量调整,41.6%,1,次,CAP,剂量调整,40.1%,31.5%,因为治疗相关不良（,TEAE,）反应终止,UTD1,治疗,29.6